Drug bioavailability and disposition vary according to body weight and weight loss after bariatric surgery. This study evaluates the impact of body weight and weight loss on the pharmacokinetics of various probe drugs, and compares these effects in three groups of patients receiving either a gall bladder operation, gastric bypass or a very low calorie diet.

This study aims to

1. to investigate the relationship between body composition and the liver/intestine activity and expression of proteins (drug metabolizing enzymes, transporters and regulatory factors) important for drug bioavailability and disposition in the range from normal to morbid obesity (the combined gastric bypass and cholecystectomy groups) at baseline.
2. to compare the short-term (6-week) and long-term (2 years) effect of gastric bypass (GBP) and a very low calorie diet (VLCD) (matched weight loss) on bioavailability and pharmacokinetics of probe drugs (caffeine, omeprazole, digoxin, midazolam, rosuvastatin, losartan) and biomarkers (and adjoining protein expressions) for cytochrome P450 (CYP)1A2, CYP2C9, CYP2C19, CYP3A, P-glycoprotein (gp) and organic anion-transporting polypeptide (OATP)1B1.
3. to compare the 3 study groups (GBP, VLCD and cholecystectomy) at baseline with respect to body composition, cardiovascular risk factors and metabolic biomarkers.
4. to compare the short-term (6-week) changes in glucose metabolism, blood pressure, blood lipids and body composition of matched weight loss and long-term effects (2 year) on body composition, cardiovascular risk factors and metabolic biomarkers, between the GBP and VLCD groups.

Inclusion Criteria:

1. Patients scheduled for GBP surgery or VLCD intervention for obesity as well as patients scheduled for cholecystectomy.
2. BMI ≥ 18.5 kg/m2
3. Able and willing to donate biopsies (as specified in the protocol) and for the GBP and VLCD patients also willing to perform follow-up 24 hour PK-investigations and other assessments as required by the clinical study protocol
4. Stable body weight (< 5 kg self reported weight change) during the last 3 months before inclusion.
5. Signed informed consent.

Exclusion Criteria:

• Concomitant treatment with drugs (according to available literature, appendix 3) and/or other factors that may influence the cocktail drug pharmacokinetics such as grapefruit juice, Seville oranges, Pomelo juice, St. Johns wort, tobacco and coffee/tea in close approximation to the investigations.
• Bradyarrhythmia, Wolff-Parkinson-White (WPW)-syndrome, atrioventricular block 2-3.
• Electrolyte disturbances (particularly hypokalemia or hypomagnesemia).
• Renal impairment: eGFR < 30 mL/min.
• Blood donations the last 4 months.
• Previous bariatric or upper gastrointestinal surgery.
• Diabetic patients treated with glitazones, insulin or sulfonylureas.
• Pregnancy (checked with HCG in urine at screening) and breast-feeding mothers.
• Known hypersensitivity (including allergy) to drugs included in the cocktail and/or local anesthesia.
• Anticoagulants with associated risk in combination with biopsies.
• Non-compliance with regards to visits and/or diet.